Developmental neurotoxicity of low dose diazinon exposure of neonatal rats: Effects on serotonin systems in adolescence and adulthood

Abstract

The developmental neurotoxicity of organophosphate pesticides targets serotonin (5HT) systems, which are involved in emotional and appetitive behaviors. We exposed neonatal rats to daily doses of diazinon on postnatal days 1-4, using doses (0.5 or 2 mg/kg) spanning the threshold for barelydetectable cholinesterase inhibition. We then evaluated the effects on 5HT 1A and 5HT 2 receptors, and on the 5HT transporter in cerebral cortical regions and the brainstem in adolescence through adulthood. Diazinon evoked a lasting deficit in 5HT 1A receptors in males only, whereas it caused a small but significant increase in 5HT transporters in females; neither effect showed a significant regional selectivity. This pattern differed substantially from that seen in earlier work with another organophosphate, chlorpyrifos, which at pharmacodynamically similar doses spanning the threshold for cholinesterase inhibition, evoked a much more substantial, global upregulation of 5HT receptor expression; with chlorpyrifos, effects on receptors were seen in females, albeit to a lesser extent than in males, and were also regionally distinct. The effects of diazinon were nonmonotonic, showing larger alterations at the lower dose, likely reflecting positive trophic effects of cholinergic stimulation once the threshold for cholinesterase inhibition is exceeded. Our results reinforce the idea that different organophosphates have fundamentally distinct effects on the developmental trajectories of specific neurotransmitter systems, unrelated to their shared action as cholinesterase inhibitors. The effects on 5HT circuits expands the scope of behavioral endpoints that need to be considered in evaluating the developmental neurotoxicity of organophosphates.

Developmental exposure to organophosphate flame retardants causes behavioral effects in larval and adult zebrafish

“…Early-life exposure to two other OP pesticides, parathion and diazinon, produce varied responses that fit the theme of altered reward salience, including decreased preference for chocolate milk over water, reduced latencies to begin eating in an unfamiliar environment, greater time in the open arms of an elevated plus maze, reduced startle response, and decreased reward-motivated spatial discrimination learning (Roegge et al, 2008; Timofeeva et al, 2008a,b). All three compounds were also found to alter the normal development of serotonin systems in rodents (Slotkin et al, 2006; Slotkin et al, 2008; Slotkin et al, 2009). These neurochemical alterations have been partially mirrored in zebrafish, as developmental exposure to chlorpyrifos lowers both serotonin and dopamine levels in larval zebrafish, with the dopamine deficits lasting through adulthood (Eddins et al, 2010).…”

The Influence of Sensitization on Mechanisms of Organophosphorus Pesticide–Induced Airway Hyperreactivity

“…One potential explanation for the discrepant dose-response relationship between studies is that male guinea pigs were used in the previous study (16), whereas female guinea pigs were used in this study. There are sex differences in the incidence of asthma (36,37) and, similarly, there are sex differences in susceptibility to pesticides (38,39).…”

Sex-Specific Neurotoxic Effects of Organophosphate Pesticides Across the Life Course

“…In regards to the serotonergic system, PND1-4 exposure to DZ resulted in a significant decrease in 5HT1A receptors in males at the lower dose administered, whereas females showed an opposite trend [92]. Sex differences in neurochemical evaluations were also reported in response to early postnatal parathion exposure [71].…”